Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: From Epidemiology to Diagnostic Approach
Abstract
:Simple Summary
Abstract
1. Introduction
2. Epidemiology
3. Pathogenesis
3.1. Genetic Background
3.2. Metabolic Disbalance
3.3. The Role of Gut Microbiota
3.4. Immune-Mediated Mechanisms
4. Clinical Picture and Outcomes
4.1. Clinical Presentation of HCC in NAFLD
4.2. Clinical Outcomes of Patients with NAFLD-Related HCC
5. Diagnostic Approach
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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HCC Cases Attributable to NAFLD | ||||
---|---|---|---|---|
Region | Investigated Population | Year/Period | Prevalence (%) | Reference |
North America Europe Asia–Pacific Africa | Multicentric study with 42 sites included in 14 countries across the world involving 18,031 patients diagnosed with HCC. | 2012–2015 | 12 10 1–6 12–22 | [20] |
United States | 4406 HCC patients identified within a healthcare claims database covering 18 million lives yearly and all US census regions. | 2002–2008 | 58 | [19] |
United States | 26,121 transplanted or waitlisted patients with HCC identified from the Scientific Registry of Transplant Recipients. | 2002 2017 | 2.1 16.2 | [21] |
United Kingdom | 632 HCC patients consecutively presented at the multidisciplinary team covering North East England, Cumbria and North Yorkshire. | 2000 2010 | <8 34.8 | |
France | 323 consecutive patients who underwent liver resection due to HCC at two tertiary centers in Paris over a 20-year period. | 1995–1999 2010-2014 | 2.6 19.5 | [22] [23] |
HCC Arising in the Absence of Cirrhosis | ||||
Germany United States Japan Germany South Korea | Systematic review with meta-analysis: 19 studies with 168 571 participants and available data about the presence of HCC among patients with/without cirrhosis; 13,345 patients had NAFLD; overall prevalence of HCC in non-cirrhotic NAFLD was 38%. | 2007–2008 2000–2010 2006–2009 1994–2013 2005–2012 | 41.7 26.9 38 13.9 34.3 | [24] |
Mechanisms | Role in Pathogenesis | |
---|---|---|
Single Gene Mutation | PNPLA3, rs738409, p.Ile148Met, chr22 | Increased liver lipid accumulation with a predisposition toward fatty hepatic diseases (NAFLD, NASH, HCC). Influences liver storage of retinol in obese patients, with role in HCC stellate cells to be investigated. |
TM6SF2, rs58542926, p.E167K, chr19p13.11 | Influences steatosis and advanced fibrosis, independently of DM, obesity or PNPLA3 genotype. Shown in hepatic injury in NAFLD-related HCC, without a clear role in HCC progression. | |
HFE H63D, rs1799945, chr6p21.3 | Found in non-cirrhotic HCC and led to hepatic inflammation, fibrosis and carcinogensis due to increased parenchymal iron accumulation. | |
rs641738, chr19q13.42 | Severe liver damage and increased fibrosis risk in NAFLD, with a further investigation regarding HCC progression. | |
Genetic Instability | DNA amplification of genes involved in oncogenic mechanisms (TERT, VGFA, MET, MYC) | Inducements for NAFLD-related HCC. |
Oncogene mutations (CTNNB1, AXIN1, ALB, TP53, CDKN2A) | ||
XPO4 and PDE1B genes | Identified in NAFLD-related HCC; unknown physiological roles in NAFLD-related HCC. | |
Epigenetic Changes | CHD1 gene | DNA methylation leading to gene silencing; related to DNA damage and repair, lipid and glucose metabolism and fibrosis progression. |
Dysregulated microRNA Expression | Downregulated liver-specific miR-122 | Reduced expression in NAFLD with negatively regulated hepatic lipogenesis. |
Other miRNAs’ altered expression (miR-21, miR-29, miR-23, miR-155, miR-221, miR-222, miR-106, miR-93, miR-519) | Major hepatocarcinogenic pathways with several targeting the PTEN protein. |
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Grgurevic, I.; Bozin, T.; Mikus, M.; Kukla, M.; O’Beirne, J. Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: From Epidemiology to Diagnostic Approach. Cancers 2021, 13, 5844. https://doi.org/10.3390/cancers13225844
Grgurevic I, Bozin T, Mikus M, Kukla M, O’Beirne J. Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: From Epidemiology to Diagnostic Approach. Cancers. 2021; 13(22):5844. https://doi.org/10.3390/cancers13225844
Chicago/Turabian StyleGrgurevic, Ivica, Tonci Bozin, Mislav Mikus, Michal Kukla, and James O’Beirne. 2021. "Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: From Epidemiology to Diagnostic Approach" Cancers 13, no. 22: 5844. https://doi.org/10.3390/cancers13225844